Organic nitrates (esters of nitric acid) are proven medicinal substances for the treatment of heart diseases. They display their effect both by relieving the heart via a reduction in the preload and afterload and by improving the oxygen supply to the heart via coronary dilatation.
However, it has been found that the classical organic nitrates used in therapy, such as glycerol trinitrate, isosorbide dinitrate or isosorbide 5-mononitrate, display, on continuous intake of high doses, within a short time a distinct attenuation of the effect, nitrate tolerance. It has been possible to eliminate this deficiency using the compounds made available by EP 0 362 575 and EP 0 451 760.
According to EP 0 362 575 and EP 0 451 760, the effect of the nitro compounds is mediated by NO free radicals formed therefrom. Reaction of the nitrates with the thiol group of cysteine initially results in the formation of a reactive and short-lived intermediate product which is still hypothetical and is presumably the thiol ester of nitric acid or a thionitrate, which undergoes intramolecular rearrangement and subsequently decomposes to a pharmacologically active NO free radical and an unstable thio free radical which reacts with other thio free radicals to give the corresponding disulphide. The formation and release of the NO free radical requires a reduced thiol group-containing cysteine, which is converted into disulphides, so that the decrease in the effect of nitro compounds on continuing intake or administration of high doses is attributed to an exhaustion of the SH group pool. EP 0 362 575 and EP 0 451 760 claim compounds which contain sulphydryl groups and, on the basis of this general structural principle, prevent nitrate tolerance or diminish a nitrate tolerance which has already occurred.